Abstract
Human enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the major etiological agents of hand, foot and mouth disease (HFMD) and are often associated with neurological complications. Currently, several vaccine types are being developed for EV71 and CA16. In this study, we constructed a bivalent chimeric virus-like particle (VLP) presenting the VP1 (aa208-222) and VP2 (aa141-155) epitopes of EV71 using hepatitis B virus core protein (HBc) as a carrier, designated HBc-E1/2. Immunization with the chimeric VLPs HBc-E1/2 induced higher IgG titers and neutralization titers against EV71 and CA16 in vitro than immunization with only one epitope incorporated into HBc. Importantly, passive immunization with the recombinant HBc-E2 particles protected neonatal mice against lethal EV71 and CA16 infections. We demonstrate that anti-VP2 (aa141-155) sera bound authentic CA16 viral particles, whereas anti-VP1 (aa208-222) sera could not. Moreover, the anti-VP2 (aa141-155) antibodies inhibited the binding of human serum to virions, which demonstrated that the VP2 epitope is immunodominant between EV71 and CA16. These results illustrated that the chimeric VLP HBc-E1/2 is a promising candidate for a broad-spectrum HFMD vaccine, and also reveals mechanisms of protection by the neighboring linear epitopes of the VP1 GH and VP2 EF loops.
Highlights
enterovirus 71 (EV71) reportedly consists of four capsid proteins VP1, VP2, VP3 and VP4, which make it a typical member of the virus family Picornaviridae
We demonstrate that the mechanism of protection conferred by hepatitis B virus core protein (HBc)-E1/2 and HBc-E2 is partly attributable to the ability to cross-neutralize and bind both EV71 and coxsackievirus A16 (CA16) viral particles, which is an ability that was lacking in HBc-E1
Previous studies reported that immunization with the synthetic peptide SP70 of EV71-VP1 elicited cross-neutralizing antibodies in vitro and that vaccination with this peptide confers cross-protection in vivo against homologous and heterologous EV71 strains in suckling BALB/c mice[16,23]
Summary
EV71 reportedly consists of four capsid proteins VP1, VP2, VP3 and VP4, which make it a typical member of the virus family Picornaviridae. Among these capsid proteins, VP1 is believed to be the major contributor to viral pathogenesis, containing important neutralizing epitopes[15]. Zhao et al reported that passive immunization with anti-ChiEV-A71 VLPs sera conferred full protection against lethal challenge of both EV-A71 and CVA16 infection[20]. We recently showed that immunization with the chimeric VLPs presenting VP2(aa141-155) epitope conferred potent protection against EV71 infection in vitro and in vivo[21]. We demonstrate that the mechanism of protection conferred by HBc-E1/2 and HBc-E2 is partly attributable to the ability to cross-neutralize and bind both EV71 and CA16 viral particles, which is an ability that was lacking in HBc-E1
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